Comparison of outcomes between off-pump and on-pump coronary artery bypass graft surgery using collaborative targeted maximum likelihood estimation

There are some discrepancies about the superiority of the off-pump coronary artery bypass grafting (CABG) surgery over the conventional cardiopulmonary bypass (on-pump). The aim of this study was estimating risk ratio of mortality in the off-pump coronary bypass compared with the on-pump using a causal model known as collaborative targeted maximum likelihood estimation (C-TMLE). The data of the Tehran Heart Cohort study from 2007 to 2020 was used. A collaborative targeted maximum likelihood estimation and targeted maximum likelihood estimation, and propensity score (PS) adjustment methods were used to estimate causal risk ratio adjusting for the minimum sufficient set of confounders, and the results were compared. Among 24,883 participants (73.6% male), 5566 patients died during an average of 8.2 years of follow-up. The risk ratio estimates (95% confidence intervals) by unadjusted log-binomial regression model, PS adjustment, TMLE, and C-TMLE methods were 0.86 (0.78–0.95), 0.88 (0.80–0.97), 0.88 (0.80–0.97), and 0.87(0.85–0.89), respectively. This study provides evidence for a protective effect of off-pump surgery on mortality risk for up to 8 years in diabetic and non-diabetic patients.

www.nature.com/scientificreports/CABG with cardiopulmonary bypass 8 .Moreover, the effect of CABG with and without cardiopulmonary bypass on mortality among diabetes and non-diabetes patients need more research 9 .
Confounding can be a major reason for this ambiguity about off-pump consequences.Conventional methods rely on correct specification of outcome model and can lead to biased and confounded results.There are numerous approaches for addressing this problem e.g., propensity score (PS) methods, g-formula or double-robust methods such as targeted maximum likelihood estimation (TMLE)  . PS mehods and g-formula rely on exposure and outcome modelling, respectively, and TMLE uses both of these models 32 .Failure to specify the correct model in PS methods and the bias-variance trade-off issue in TMLE leads to biased estimates for the parameter of interest and high variance when analysing a large number of variables, respectively 33,34 .Since the estimates from sparse data, regression of exposure given confounders is close to zero or one within one or more strata of covariates, can be biased, double robust estimators are not immune to light violations of the positivity assumption in sparse data.The collaborative targeted maximum-likelihood estimation (C-TMLE) addresses biased estimates from sparse data by applying the nuisance parameter estimation and decreasing mean square error (MSE) in the parameter estimate .35 C-TMLE method does not require that either the estimate of exposure or outcome be consistent, rather it focuses on the reduction of the distance between the estimate of exposure mechanism and its parameter and outcome estimate and its parameter, therefore this approach provides an unbiased and precise estimate (low standard error or narrower confidence interval) of the parameter 34 .Since C-TMLE produces stable estimates of borderline identifiable parameters and is super-efficient and also because of ambiguities about the effect of off-pump we aimed to use a stronger and more optimized double robust method, C-TMLE, for address a selected-least set of covariates and estimate the effect of the off-pump technique surgery on mortality.

Study oversight and setting
We examined the effect of off-pump CABG on death by a prospective analysis of Tehran Heart Center's Surgery data-registry with a median follow-up of 8 years.From 2007 to 2016, patients having undergone isolated CABG were involved in the cohort study by protocol and then were followed in 4, 6, and 12 postoperative months and annually afterward.Follow-ups were done by inpatient visits and face-to-face interviews or telephone contacts for patients who could not attend clinic.The data are stored in the CABG Follow-up databank, which contains classified variables such as demographics, atherosclerosis risk factors, the status of their control, ECG and routine laboratory findings, exercise test results, major events such as acute coronary syndrome, mortality, etc.The Tehran Heart Center (THC)is a major medical treatment facility in Iran that serves both local patients and those referred from other cities.In THC, 28,945 subjects with isolated first-time CABG procedures and with at least 1 graft that has been followed between March 2007 and March 2020 36 .Of these, 4062 patients with incomplete registry data, loss to complete follow-up or CABG with valve surgery were excluded.Finally, 24,883 participants were included in the analysis.
To ensure obscurity, personal identifiers such as name, phone number, and residence address were removed from the raw data, and personal identification number was converted into a serial number.Moreover, this study was approved in terms of the study protocol by the Tehran Heart Center (THC) Review Board and the ethical committee of the Tehran University of Medical Sciences (IR.TUMS.SPH.REC.1402.004).At the time of hospitalization, all patients gave written and informed consent, which included prolonged data collection in the follow-up.Using data in the present study were according to the Helsinki Declaration.

Definition of variables
We defined blood hypertension as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg or a history of prescribed antihypertensive medications.Additionally, we labeled diabetes mellitus (DM) as any one of fasting plasma sugar ≥ 126 mg/dl; or HbA1c ≥ 6.5%; taking oral hypoglycemic drugs; or injecting insulin; or random plasma glucose ≥ 200 mg/dl, any type of diabetes was considered as diabetes (9941, 39.9%).Ejection fraction was classified as normal (heart failure ≥ 55 in men and ≥ 60 in women), mildly reduced, and reduced (heart failure < 40%) 13 .Each patient with one of the following disorders was involved in the dyslipidemia group; total cholesterol level ≥ 240 mg/dl; LDL-C level of more than 160 mg/dl; triglyceride serum ≥ 200 mg/dl; and HDL-C of less than 40 mg/dl and less than 50 mg/dl in men and women, respectively; or a history of taking lipid medications based on the National Cholesterol Education Program (NCEP) Adult Treatment Plan (ATP) III 37,38 .According to the patient's self-response, we classified cigarette smoking status as never smoker and before or current smoker.Moreover, patients were labeled as opium-addicted if they reported current consumption of opium, either inhalation or oral or drinking (with water or tea).The Body Mass Index (BMI) was calculated as the individual's weight in kilograms divided by the square of the height in meters.COPD was diagnosed as incompletely reversible airflow obstruction which was confirmed by spirometry with a ratio of post-bronchodilator forced expiratory volume in one second to forced vital capacity (FEV1/FVC), 0.7, in the lack of bronchiectasis or tuberculosis to otherwise.Additionally, we consider a family history of CAD as acute myocardial infarction or recorded CAD, diagnosed by either computed tomography or invasive coronary angiography, in first-degree relatives.

Exposure
Patients with CABG on the beating heart without cardiopulmonary bypass, and off-pump coronary artery bypass (OPCAB), were defined as the exposure group.In contrast, performed CABG on patients using the on-pump technique, with cardiopulmonary bypass 39 , was classified in the unexposed group.

Analysis
Normally distributed and non-Normally distributed variables were presented as mean (SD) and median (IQR), respectively.Normality was assessed by the Kolmogorov-Smirnov test and Q-Q plot 50 .Moreover, log-binomial regression model was used for estimating unadjusted/adjusted risk ratio.Independent Student's t-test was performed for comparison of continuous variables with Normal distribution and Mann-Whitney U-test was performed for not Normally distributed.Additionally, the Pearson χ2 test was conducted for categorical variables.Markov Chain Monte Carlo-based method was used to impute the missing data of BMI (80 missing values, 0.30%), smoking status (49 missing values, 0.19%), MI (92 missing values, 0.37%), COPD (80 missing values, 0.30%), and family history (31 missing values, 0.12%).All variables in Table 1 were involved in the imputation process.
In the first step, TMLE in general form (event = 0 and event = 1) models the outcome (death) based on exposure (technique of surgery) and confounders (age, COPD, pre or current myocardial infarction, smoking, and consumption of opium) using super learner (initial estimate).Then, using a regression model of exposure on confounders (super leaner), PS is estimated and a clever covariate, known as H, is generated (step 2).In this model, the technique of surgery (exposure) is regressed on age, COPD, pre or current myocardial infarction, smoking, and consumption of opium.The predicted probability of the fitted model is PS.In the last step, the outcome model is updated (step 1) by refitting step 1 and including H in model; in the updated model, initial estimate is considered as an offset.Finally, risk ratio is estimated using standardized mean in the exposed and un-exposed groups based on the updated outcome model.
C-TMLE is extension of TMLE which attempts to avoid increasing variance by sequentially updating outcome regressions based on PS estimates that incorporate an increasing number of confounders 51 .The general C-TMLE procedure is based on the following steps; In the first step, an estimate of outcome model ( Q 0 ) on exposure (technique of surgery) and confounders (all confounders) is obtained using super learner.In the second step, a sequence of regression model of exposure ( g ) is generated, so that the confounders are included in the exposure model in a stepwise manner based on the cross-validated penalized likelihood of the outcome model .(g 1 : age , g 2 : ageandCOPD, g 3 : age, COPD, and pre or current myocardial infarction, g 4 :age, COPD, pre or current myocardial infarction, and smoking, g 5 : age, COPD, pre or current myocardial infarc- tion, smoking, and consumption of opium.).The first clever covariate is constructed by adding a confounder, the one which maximizes the penalized likelihood of the outcome model, to the exposure model.(g 1 : age).
In the third step, the outcome regression model, fitted in the first step, is updated based on the first clever covariate, with initial estimate of step 1 as offset.Next, exposure model is updated by including an additional confounder ( g 2 : ageandCOPD ).This process continues until the log-likelihood of the outcome model does not increase (until g 5 in our analysis).In the Final step, risk ratio is estimated using standardized mean in the exposed and un-exposed groups based on the last updated outcome model.identifying TMLE ( Q * ), the candidate TMLE in the sequence that minimizes the cross-validated risk and finally estimating effect measure by using outcome mean in exposure and un-exposure groups 34 .
For comparison, we estimated the PS for each patient using multivariable logistic regression model.To compare models, we calculated Akaike information criterion (AIC).A minimally sufficient set of confounders based on Fig. 1 was included as predictors and the variable surgery technique (off-pump/on-pump) was involved as the response variable.Using the PS and exposure variable in the log-binomial model, we estimated the PS-adjusted effect.Additionally, adjusted Cox proportional hazards model was performed.Standard errors for TMLE and C-TMLE were estimated using influence function, and all effect estimates were reported as risk ratio with 95% CIs [52][53][54][55][56][57] .All analyses were repeated in diabetes and non-diabetes subgroups.Statistical analysis was performed using R, version 3.5.0(R Foundation for Statistical Computing, Vienna, Austria).

Results
During the follow-up, with the median (Q1, Q3) of 8 (5.6, 11.1) years, 24,883 patients 18,318 male and 6565 female underwent isolated coronary artery surgery and were included in the Tehran Heart Center's CABG data registry.The mean (SD) age of the study participants was 65 (10.0)years, ranged from 19 to 95 years (more than 96% of patients were older than 30 years).A total of 1881 patients underwent off-pump surgery 367 (19.5%), and from 22,922 patients with on-pump, 5176 (22.6%) died during the study follow-up.The on-pump group had a longer follow-up time (8.3 (5.8, 11.2) and 6.3(5.0,7.3), respectively).Moreover, participants with off-pumps were more likely to have a BMI higher than 30 kg/m 2 (26.5% vs. 24.0%).On-pump coronary artery bypass graft surgery was associated with having a myocardial infarction, family history of CVD, and dyslipidemia.In contrast, participants who experienced a lower ejection fraction were more likely to have off-pump surgery (Table 1).Moreover, we assessed the association between study variables and surgery technique in both diabetic and non-diabetic patients.As shown in Table 2, both diabetic and non-diabetic participants who underwent on-pump CABG were more likely to die than the off-pump group.In addition, the high body mass index was associated with taking off-pump surgery in non-diabetic patients.Moreover, Table 2 indicates that patients with diabetes who have hypertension had an increased probability of undergoing off-pump CABG.
To assess the potential violation of the positivity assumption, the distribution of PS for both on-pump and off-pump groups has been depicted in Fig. 2. The median (IQR) for both groups are 0.081(0.059,0.084) and 0.082 (0.060, 0.084), respectively.The minimum value (0.054) and maximum value (0.1) were almost equal.In general, both distributions are very similar so that PS values were mostly lower than 0.1 and bimodal nearly in 0.06 and 0.08.The effect estimates of surgery technique on the risk of mortality along with 95% CIs have been estimated by four statistical methods, presented in Table 3: unadjusted, PS-adjusted, TMLE and C-TMLE, for subgroups of diabetes and non-diabetes patients as well as Total sample.
The Cox proportional hazards model shows a higher hazard of mortality for the off-pump technique, with HR = 1.31, 95% CI 1.10-1.55 in diabetes patients, HR = 1.21, 95% CI 1.02-1.43 in non-diabetes patients, and HR = 1.24, 95% CI 1.10-1.40 in the total sample.Proportional hazards assumptions were confirmed using scaled Schoenfeld residuals (The p-values were 0.13, 0.73, and 0.26 in the total, diabetes, and non-diabetes, respectively).

Figure 1 .
Figure 1.Causal directed acyclic graph for the effect of the surgery technique on death.

Figure 2 .
Figure 2. Histogram distribution of propensity score by surgery technique.

Table 1 .
Descriptive characteristics of the patients (n = 24,803) in Tehran Heart Cohort study based on surgery technique.No. (%) has been reported for description of the variables, unless otherwise stated.$ Myocardial Infarction # History of cardiovascular disease, MI, and stroke in first-degree relatives.Pearson χ2 test, Independent Student's t-test, and Mann-Whitney U-test.

Table 2 .
Association between study variables and technique of surgery in diabetes subgroups.No. (%) has been reported for description of the variables, unless otherwise stated.$Myocardial Infarction.#History of cardiovascular disease, MI, and stroke in first-degree relatives.Pearson χ2 test, Independent Student's t-test, and Mann-Whitney U-test.